BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development

Autor: Yoshihiro Komatsu, Kohei Kitami, Megumi Kitami, Masaru Kaku, Bin Wang
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Embryology
DNA Repair
Craniofacial abnormality
Organogenesis
Biochemistry
Craniofacial Abnormalities
0302 clinical medicine
Cranial neural crest
Neural Stem Cells
Animal Cells
Osteogenesis
Medicine and Health Sciences
skin and connective tissue diseases
Musculoskeletal System
Genetics (clinical)
Cells
Cultured
Mice
Knockout
BRCA1 Protein
Cancer Risk Factors
Stem Cells
Neural crest
Gene Expression Regulation
Developmental
Cell biology
Nucleic acids
medicine.anatomical_structure
Oncology
Neural Crest
Anatomy
Cellular Types
Research Article
lcsh:QH426-470
DNA damage
Genetic Causes of Cancer
Mice
Transgenic
Biology
03 medical and health sciences
Developmental Neuroscience
medicine
Genetics
Animals
Craniofacial
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Skeleton
Cell Proliferation
BRCA2 Protein
Bone Development
Biology and life sciences
Mesenchymal stem cell
Embryos
Skull
Mesenchymal Stem Cells
DNA
Cell Biology
medicine.disease
lcsh:Genetics
030104 developmental biology
Multipotent Stem Cell
Face
Cellular Neuroscience
Frontal Bones
Organism Development
Head
030217 neurology & neurosurgery
Developmental Biology
Neuroscience
Zdroj: PLoS Genetics
PLoS Genetics, Vol 14, Iss 5, p e1007340 (2018)
ISSN: 1553-7404
1553-7390
Popis: Craniofacial abnormalities, including facial skeletal defects, comprise approximately one-third of all birth defects in humans. Since most bones in the face derive from cranial neural crest cells (CNCCs), which are multipotent stem cells, craniofacial bone disorders are largely attributed to defects in CNCCs. However, it remains unclear how the niche of CNCCs is coordinated by multiple gene regulatory networks essential for craniofacial bone development. Here we report that tumor suppressors breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are required for craniofacial bone development in mice. Disruption of Brca1 in CNCC-derived mesenchymal cells, but not in epithelial-derived cells, resulted in craniofacial skeletal defects. Whereas osteogenic differentiation was normal, both osteogenic proliferation and survival were severely attenuated in Brca1 mutants. Brca1-deficient craniofacial skeletogenic precursors displayed increased DNA damage and enhanced cell apoptosis. Importantly, the craniofacial skeletal defects were sufficiently rescued by superimposing p53 null alleles in a neural crest-specific manner in vivo, indicating that BRCA1 deficiency induced DNA damage, cell apoptosis, and that the pathogenesis of craniofacial bone defects can be compensated by inactivation of p53. Mice lacking Brca2 in CNCCs, but not in epithelial-derived cells, also displayed abnormalities resembling the craniofacial skeletal malformations observed in Brca1 mutants. Our data shed light on the importance of BRCA1/BRCA2 function in CNCCs during craniofacial skeletal formation.
Author summary Craniofacial abnormalities, including facial skeletal defects, comprise approximately one-third of all birth defects in humans. Since most bones in the face derive from neural crest cells, which are multipotent stem cells, craniofacial bone disorders are largely attributed to defects in neural crest cells. However, it remains unclear how the niche of neural crest cells is coordinated by multiple gene regulatory networks essential for craniofacial bone development. Here, we show that tumor suppressor breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are required for craniofacial bone development in mice. Our data shed light on the importance of the DNA damage response/repair machinery in neural crest cells via BRCA1/BRCA2, providing novel insights into the mechanisms of craniofacial bone development.
Databáze: OpenAIRE
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